In one study only five percent of a large sample of dogs below thirty pounds had osteosarcoma."Giant
breed dogs, weighing more than 90 lb, accounted for 29% of the cases of osteosarcoma"."Large
breed dogs, weighing 60 lb to 901b, accounted for 55% of the cases of osteosarcoma."
"Medium breed dogs weighing 30 lb to 60 lb accounted for 11% of the cases
of canine osteosarcoma." In May of 1999, I, J.P. Morgan(D.O.B 1988),a mini
schnauzer started limping. I couldn't hide the pain. For eleven years I
play fought with my littermate Hammy and finally I paid the price for all
that fun. He was always bigger but I held my own. He was always fiercer but
I was always determined to hold my own and I DID!
My vet and companion assumed my limping was result of an injury that should
heal and that was that. Sure enough I could compensate for the pain and was
back to jumping and getting on the dining room table for the cats' food (i
knew Bobby was pleased with my agility-she could never wipe the smiles off
her face at my feats)... until the next episode with occasional intermittent
limping- this time when I was chasing a puppy around-you can't believe the
fun or the price. I no longer could put any weight on my right back leg (you
should have seen her face then-pure guilt ridden-she didn't get it..til much
later-my last blast-)-Bobby, my companion if you were guessing, brought
me to the vet and xrays were taken. The xrays showed the bone had been eaten
away and the tentative diagnosis was osteosarcoma-bone cancer. They say about
10,000 dogs a year get it a year but I bet more do. Usually large breed dogs
get osteosarcoma in their front legs which bear their weight. At most, I
weighed only 23 pounds and I got it in my back leg. I must admit I boxer
fought with my littermate Hammy all my life until I got osteosarcoma, OS
for short, so a lot of weight was put on my back legs. Since I had a
heart condition-my vet vetoed bone biopsy-he also didn't sedate me for the
x-ray.I loved his sense of human humor..-he joked we could perfect x-rays
but because of my heart-a dead dog-A second set of x-rays were given a month
and a half later. The diagnosis was changed to bone cancer but not osteosarcoma.He
still referred to me as a tripod..most of us become tripods because of disuse
of the leg or amputation. Thank goodness Bobby never called me "her little
tripod" but continued throughout the next two and half years to give me my
dignity. Of course, I didn't mind the nonstop loving attention. I know I
gave myself again as to how much I loved her because all the times she looked
at me she caught me looking at her. Geez..my tough image was hard to maintain!
Usually osteosarcoma spreads quickly to the lungs and when the diagnosis
is made, we usually only have a few months to live. Since Bobby has been
reading the canine bone cancer thread for over three plus years, she has
repeatedly heard companions told this but has hardly read this happen.
Because of the aggressive of the bone damage, my vet changed the diagnosis
to tentatively fibrosarcoma because my lungs were clear. Later Bobby,
my companion, found research that once again suggested that it was osteosarcoma.
She showed my vet an abstract of eight schnauzers with OS in the back leg
and an xray picture seemingly identifical to mine...makes you wonder how
many different forms of OS there are and if some are less aggressive than
others. Also there is research suggesting that amputation or radiation without
accompanying chemo may help the cancer to spread. Because of my heart and
age, I had neither. *-Fungal infection was ruled out(valley-fever-Coccidioidomycosis(I
hadn't been to southwest which has avirulent fungus which could do that type
of bone rotting-tick disease imitator ruled out-hadn't been in tick country
not did I have any of the symptoms that usually accompanied it..-My companion
continued to do a lot of research. She was horrified to learn that that
oversupplementation of puppies might help cause limping. Too many calcium
supplements for instance. She even read one study blaming vaccination for
HOD..which appeared about twenty years ago.. She has been writing a couple
of pages with research abstracts on HOD(hypertrophic osteodystrophy) and
limping to show what she has found....HOD and calcium and puppies.excellent writeup on lameness and possible causesPlease
have your companion read them to help other pups down the road. They love
us so much and try their best..sometimes they can hurt us with their kindness....
-again except for lameness-no other symptoms were present-osteomyelitis
was also ruled out-again none of the symptoms- no prior trauma (often times
osteosarcoma is preceded with a bone trauma( often dogs have metal pins or
plates)-my companion thinks mine was from stress on back leg from all the
play fighting-ie bone break etc to a limb. The x-rays were sent for a free
reading to a California vet hospital and the canine radiologist also felt
it was bone cancer

RADIOGRAPHSMarvistavet's has excellent description of what xray's look like. Mine looked like the lytic lesion-"The “lytic lesion” – looks like an area of bone has been eaten away.
The “sunburst” pattern – shows as a corona effect as the tumor grows outward and pushes the more normal outer bone up and away.
Apathologic fracture may be seen through the abnormal bone.
Osteosarcoma does not cross the joint space to affect other bones comprising the joint.
In most cases, radiography is all that is needed to make the diagnosis but sometimes there are ambiguities"

At that point the rollcoaster ride began for my companion The vet had
told my companion that he didn't expect me to live past last February 2000.
Did I ever fool him. I made it to Dec 14, 2001 and it wasn't the cancer that
got me. My heart just tired. My vet perscribed Rimadyl as the painkiller.
In his practice,he found that Feldene-although it has some possibly anti
tumor properties,caused too many GI upsets. My breed wasn't as much at risk
for the dangers of rimadyl. That is questionable. Labs are one of the most
population breeds-as of 1999 Rimadyl was perscribed to four million dogs-no
statistical analysis has been done since vets are not required to keep records
of what breed of dog they prescribe the medication. So Labs might rank high
for reported incidents-but we don't know of ratio of how many Labs haven't
had side effects.

My companion also has read that
NSAIDS..rimadyl is one..may have anti tumor properties and anti cachexia
properties...besides pain control. My vet ruled out amputation because
of my heart condition. Otherwise, it have been amputated and spared me the
extra weight of carrying it around,spared me the pain of the bone cancer,and
spared my companions's being so protective of that leg and having to compensate
for keeping that leg out of harm's way. She would have been spared the terror
of a possible fracture,worrying when other dogs wanted to play with me,worrying
about people possibly bumping into the leg with strollers etc-worrying about
how to keep the leg clean-(I sometimes couldn't get the leg out of pee's
way and brother did I hate having my legs groomed.)
One cold winter night,a golden safety net was thrown to my companion. She met a Canadian holistic
vet on the street who spoke to her for 20 minutes and answered as best he could all her
questions. He said that I had a chance of being treated holistically to help my little
IMMUNE SYSTEM battle the cancer. The vet recommended Wysong dog food,fresh food,flaxseed
oil and cottage cheese and supplements to help boost my immune system and also my heart!. Then my companion started
nonstop research started-re detoxifying my body,finding natural remedies
such as herbs etc. Later she found out about Professional Anti-Slip Spray
$6.20
BIO52308
Show Foot Anti-Slip spray for shows. . She didn't need to buy it for me or scatter rugs around the apartment since the floors were already carpeted and I wasn't slipping using my three legs. I thought I should mention it to you in case you are slipping on slippery tiles or whatever. (Many of the links on found on the main page of ThenSome's Pethealth Links

Without Regret : A Handbook for Owners of Canine Amputees

I am assuming that no morevaccinations
, a cancer starving diet, supplements, rest, and not bombarding my immune
system with invasive tests, chemo, sedation, surgery, or radiation has helped
me to beat the odds and let my immune system to just concentrate on the
battle against cancer. She read everything on holistic supplements and read
and read and read and then applied what she read

For the first year, I slept a great deal...yes I was in discomfort but not pain like the first three months.
I am pretty sure I beat the cancer.I
didn't want anybody to know how bad the pain was so I usually went into a
corner and slept and prepared myself the the next walk and sniff. Bobby didn't
have a clue how badly it hurt. I must admit I was a master at hiding the
pain. We dogs are pretty clever. I figured how to lift my leg at three months..who
needs to wet themselves with urine flow if you can move your leg out of the
direction. No squatting for me. Same with holding up your leg. I figured
if I didn't put weight on my leg..it wouldn't hurt.I knew she was throwing
all those supplements in the cottage cheese but I didn't care. I was being
fed first for the first time in my life and Hammy let me. She gave me a ton
of anti virals and anti inflammatories and anti virals...I think the anti
inflammatories helped big time..the omega threes in flaxseed and fish oil
and the NSAID rimadyl and also the heart medication. She collected some inflammation
and cancer links links here.
There is an article on that page that suggests fish oil can cause oxidative stress which can be a negative, although sometimes a positive.
(She still hasn't stopped with the research. She would have added alpha lipoic
acid as an powerful antioxidant if she had known about it-it is cheaper than
coenzyme q 10)

She found two interesting research articles one alpha lipoic acid which I told her to plunk right here if you think you might be going for chemotherapy..you might want to show the two to your vet.WASHINGTON (Reuters Health) - A drop in sex hormones may increase the risk of a type of bone cancer, according to results of a study conducted in purebred Rottweilers. The highly malignant bone cancer, known as osteosarcoma, has noticeable similarities in both humans and Rottweilers, researchers at Purdue University reported at a meeting of the Gerontological Society of America.
In a study of 745 purebred Rottweilers, Dr. B. C. Beranek and colleagues from the departments of veterinary clinical science and veterinary pathology found that 15% of all the dogs developed bone cancer. However, the risk of bone cancer was 65% higher for castrated males and 34% higher for spayed females. The risk of developing bone cancer was higher both in females spayed at less than one year of age as well as males castrated when they
were less than a year old compared with animals who were not spayed or neutered.
It is not clear why spaying or neutering had an impact on cancer risk, but it may be related to their lower levels of sex hormones. More study is needed to determine if these factors play any role in human cancerOncol Rep. 2005 Feb;13(2):253-7. :
Antitumor effect of nutrient synergy on human osteosarcoma cells U-2OS, MNNG-HOS and Ewing's sarcoma SK-ES.1.
Roomi MW, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M.
Matthias Rath Research, Cancer Division, 1260 Memorex Drive, Santa Clara, CA 95050, USA.Current treatment of osteosarcoma is associated with poor prognosis, especially due to the increased risk of developing other cancers with chemotherapy. Therefore, new, safe and effective treatment strategies are needed. We investigated the effect of a unique mixture of nutrients containing lysine, proline, arginine, ascorbic acid, and epigallocatechin gallate (EGCG) on human osteosarcoma cell lines U-2OS, MNNG-HOS, and Ewing's sarcoma SK-ES-1 by measuring: cell proliferation, expression of matrix metalloproteinase-2 (MMP-2), MMP-9, and invasive and angiogenesis potential. Cell proliferation was evaluated by MTT assay, matrix metalloproteinases (MMP) expression by gelatinase zymography, VEGF expression by ELISA, and invasion through Matrigel. Cells were also treated with phorbol 12-myristate 13-acetate (PMA) to study enhanced MMP and VEGF expression. The invasion of osteosarcoma U-2OS and MNNG-HOS cells through Matrigel was significantly reduced in a dose-dependent fashion, with 100% inhibition of invasion of U-2OS cells at 100 microg/ml, and MNNG cells at 50 microg/ml concentration of the synergistically acting nutrient mixture. Ewing's sarcoma SK-ES-1 cells were not invasive. Nutrient synergy (NS) exhibited a dose response antiproliferative effect on osteosarcoma U-2OS cells, reaching 67% at 1000 microg/ml of NS; no significant suppression of cell proliferation was seen with MNNG or Ewing's sarcoma cells. Zymography showed dose-dependent inhibition of MMP secretion by all three cell lines in the presence of NS. VEGF secretion by U-2OS cells was completely blocked at 500 microg/ml of NS. Our results suggest NS is an excellent candidate for therapeutic use in the treatment of osteosarcoma, by inhibiting cancer cell invasion, and secretion of MMPs and VEGF, all critical parameters for cancer control and prevention.
1: J Am Vet Med Assoc. 2004 Nov 15;225(10):1567-72, 1548. :
Stereotactic radiosurgery for treatment of osteosarcomas involving the distal portions of the limbs in dogs.
Farese JP, Milner R, Thompson MS, Lester N, Cooke K, Fox L, Hester J, Bova FJ.
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0126, USA.Stereotactic radiosurgery (SRS) involves precise delivery of a single large dose of radiation to a designated tumor target. This report describes use of SRS in combination with a frameless stereotactic localization system to treat 11 dogs with appendicular osteosarcomas. Five dogs were treated with SRS alone; 6 were treated with a combination of SRS and chemotherapy. Overall median survival time was 363 days (range, 145 to 763 days), with 6 dogs still alive 90, 142, 234, 367, 633, and 763 days after SRS. Limb function was good or excellent in all 6 dogs that were still alive. Results in these dogs suggest that SRS may be a viable option for dogs with appendicular osteosarcoma, with the potential to provide long-term local tumor control and improvement in limb function, especially when combined with chemotherapy. Because of the destructive nature of osteosarcoma and limitations of SRS, dogs with tumors that are small and have caused minimal bone destruction would likely be the best candidates for this procedure.
Am J Vet Res. 2004 May;65(5):659-64. :
Effect of thalidomide on growth and metastasis of canine osteosarcoma cells after xenotransplantation in athymic mice.
Farese JP, Fox LE, Detrisac CJ, Van Gilder JM, Roberts SL, Baldwin JM.
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USAOBJECTIVE: To determine whether thalidomide inhibits the growth of primary and pulmonary metastatic canine osteosarcoma in mice after xenotransplantation. ANIMALS: Athymic nude mice. PROCEDURE: Canine osteosarcoma cells were injected SC in 50 mice. Mice were randomly placed into the following groups: control group (n = 13; DMSO [drug vehicle] alone [0.1 mL/d, IP]); low-dose group (12; thalidomide [100 mg/kg, IP]), mid-dose group (13; thalidomide [200 mg/kg, IP]); and high-dose group (12; thalidomide [400 mg/kg, IP]). Starting on day 8, treatments were administered daily and tumor measurements were performed for 20 days. On day 28, mice were euthanatized and primary tumors were weighed. Lungs were examined histologically to determine the number of mice with metastasis and tumor emboli. Mean area of the pulmonary micrometastatic foci was determined for mice from each group. RESULTS: Primary tumor size and weight were not significantly different among groups. The number of mice in the mid-dose (200 mg/kg) and high-dose (400 mg/kg) groups with micrometastasis was significantly less than the number of control group mice; however, the number of mice with tumor emboli was not affected by thalidomide treatment. Size of micrometastasis lesions was not affected by thalidomide treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Mean area of micrometastases was not affected by treatment; however, growth of micrometastases had not yet reached an angiogenesis-dependent size. Although thalidomide did not affect growth of primary tumors in mice after xenotransplantation of canine osteosarcoma cells, our findings indicate that thalidomide may interfere with the ability of embolic tumor cells to complete the metastatic process within the lungs
Exp Eye Res. 2003 Feb;76(2):241-8. :
Alpha lipoic acid changes iron uptake and storage in lens epithelial cells.
Goralska M, Dackor R, Holley B, McGahan MC.
Department of Molecular Biomedical Sciences, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA.
Alpha lipoic acid (LA) is a cofactor in mitochondrial dehydrogenase complexes. Previous studies have shown that when administered exogenously LA has antioxidant properties, which include free radical scavenging, metal chelation and regeneration of other antioxidants. The cells convert LA into dihydroplipoic acid (DHLA), which in the presence of iron can act as a prooxidant. In vitro DHLA reduces Fe(+3) to Fe(+2) and removes iron from ferritin, increasing the risk of Fe catalyzed free radical formation. In the present study we examined the in vivo effects of lipoic acid treatment on Fe metabolism in cultured lens epithelial cells, and found that LA decreases Fe uptake from transferrin, increases Fe deposition into ferritin and increases the concentration of this protein. When administered together with ascorbic acid, lipoic acid changes the characteristic heavy to light chain ratio of ferritin makeup. The decreased Fe uptake and increased storage diminishes the size of the cytosolic highly reactive Fe pool (LIP). These changes are associated with increased cell resistance to H(2)O(2) challenge. Therefore, LA may reduce the risk of Fe induced oxidative damage and also might be useful as a treatment of Fe overload. Copyright 2003 Elsevier Science Ltd.Mol Pharmacol. 2003 Apr;63(4):849-61. :
Anthracyclines induce accumulation of iron in ferritin in myocardial and neoplastic cells: inhibition of the ferritin iron mobilization pathway.
Kwok JC, Richardson DR.
The Heart Research Institute, Iron Metabolism and Chelation Group, Sydney, New South Wales, Australia.
Anthracyclines are potent antitumor agents that cause cardiotoxicity at high cumulative doses. Because anthracycline cardiotoxicity is attributed to their ability to avidly bind iron (Fe), we examined the effect of anthracyclines on intracellular Fe trafficking in neoplastic cells and differentiated cardiomyocytes. In both cell types, incubation with doxorubicin (DOX) resulted in a significant (p < 0.004) accumulation of Fe in the storage protein, ferritin. Pulse-chase experiments using control cells demonstrated that within 6 h, the majority of (59)Fe donated from transferrin was incorporated into ferritin. Over longer incubation periods up to 18 to 24 h, (59)Fe was subsequently mobilized from ferritin into other compartments in control cells. However, anthracyclines inhibited ferritin-(59)Fe redistribution during the 18- to 24-h period, resulting in a significant (p < 0.0003) 3- to 5-fold accumulation of ferritin-(59)Fe compared with control cells. The increase in ferritin-(59)Fe after a 24-h incubation with DOX could not be correlated with increased ferritin expression, suggesting that (59)Fe accumulation occurred in pre-existing ferritin. In addition to DOX, other redox-cycling agents (i.e., menadione and paraquat) also increased ferritin-(59)Fe levels. Moreover, the intracellular superoxide scavenger, Mn(III) tetrakis(4-benzoic acid)-porphyrin complex, partially prevented the ability of DOX and menadione at inducing this effect. Hence, superoxide generation by these compounds could play a role in causing ferritin-(59)Fe accumulation. This study is the first to demonstrate the effect of anthracyclines at inhibiting Fe mobilization from ferritin, resulting in marked Fe accumulation within the molecule. This response may have consequences in terms of the cytotoxic effects of anthracyclines.
In: Genes, Dogs and Cancer: 3rd Annual Canine Cancer Conference - 2003, Modiano J. F. (Ed.)
International Veterinary Information Service, Ithaca NY (www.ivis.org), 2003; P3003.0903
Limb Sparing Trials and Canine Osteosarcoma (Last Updated: 5-Sep-2003 )
S. J. Withrow
Animal Cancer Center, Colorado State University, Fort Collins, CO, USA.
Osteosarcoma (OSA) is a common malignancy in dogs. Clinical problems include local disease control and metastasis. Amputation and postoperative chemotherapy remain the standard of care although limb sparing has become a suitable alternative to amputation in selected cases. Controlled, randomized and prospective trials can be performed to study both local and systemic control of cancer in pet animals. Pets with cancer are attractive models because of increased incidence of some cancers (10x greater incidence of OSA in dogs versus people); pets are out bred with intact immune system; shorter time to local recurrence and metastasis (trial end points reached sooner); reduced costs (compared to human trials); owner compliance with randomization and follow-up; necropsy compliance (documentation of toxicity and outcome); large enough animals for surgical intervention and orthopedic implants; similar physiology of drug metabolism, excretion and tumor susceptibility; relative exemption from animal rights groups criticism due to spontaneous nature of disease and fact that animals often receive "state of the art" treatment plus or minus the investigational intervention.
Almost 500 dogs have undergone limb sparing for OSA in the last 20 years at CSU while several thousand had amputation for local disease control. Two separate NIH funded trials were completed involving limb sparing. The first demonstrated that preoperative radiation and intra-arterial cisplatin could induce substantial percent necrosis in the tumor; there was a radiation dose response for % tumor necrosis that was lower than that to induce normal bone necrosis and that increased tumor necrosis led to decreased local recurrence [1,2]. Another trial looked at the influence of a locally implanted biodegradable cisplatin polymer on local recurrence and demonstrated improved local control with the local chemotherapy [3].
Pet animals offer a unique and readily accessible resource of "real cancer" that are a natural bridge between invitro or rodent models and human trials. The veterinary profession is willing and capable of contributing to comparative oncology trials and has a demonstrated and creditable track record in this area.
References
1 - Thrall DE, Withrow SJ, Powers BE, et al. Radiotherapy prior to cortical allograft limb sparing in dogs with osteosarcoma: a dose response assay. Int J Radiat Oncol Biol Phys 1990;18(6):1351-1357 - PubMed -
2 - Withrow SJ, Thrall DE, Straw RC, et al. Intra-arterial cisplatin with or without radiation in limb-sparing for canine osteosarcoma. Cancer 1993; 71(8):2484-2490. - PubMed -
3 - Withrow SJ, Liptak JM, Straw RC, et al. Biodegradable Cisplatin Polymer in Limb Saring Surgery for Canine Osteosarcoma. Clin Ortho & Related Research. Submitted, June 2003
In: Genes, Dogs and Cancer: 3rd Annual Canine Cancer Conference - 2003, Modiano J. F. (Ed.)
International Veterinary Information Service, Ithaca NY (www.ivis.org), 2003; P3039.0903
Overexpression of the erbB-2 Proto-Oncogene in Canine Osteosarcoma Cell (Last Updated: 5-Sep-2003 )
A. F. Flint1, L. UíRen2, M. E. Legare3, S. J. Withrow4, Dernell5 and W. H. Hanneman6
1,3,6Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort. Collins, CO, USA.
2,4,5Animal Cancer Center, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort. Collins, CO, USA.
Osteosarcoma (OSA) is the most frequent highly malignant bone-tumor in canine as well as human patients. The use of canine OSA as models of human OSA is compelling due to the fact that they bear the following striking resemblances: males are more commonly affected in both species; metaphyseal sites in appendicular bones are most often affected; the etiology is unknownand less than 10% of patients have documented metastasis at presentation. Over 90% of canine OSA show high grade histology with the metastatic rate more than 80% with amputation alone, primarily to the lung. Research into the molecular mechanisms underlying canine OSA would provide necessary information toward better treatment of both canine and human patients. ErbB-2 is a proto-oncogene that encodes human epidermal growth factor receptor 2 (HER-2). HER-2 is a 185 kD transmembrane glycoprotein of the tyrosine kinase family of receptors. To date no known ligand has been found for HER-2, however, activation of HER-2 induces of a cascade of mechanisms resulting in cell transformation and growth . HER-2 has been extensively evaluated in both human and canine breast cancer. In both cases HER-2 overexpression is correlated to poor prognosis. In light of these data, HER-2/erbB-2 expression maybe a useful prognostic indicator in canine OSA. We used quantitative Real-Time RT-PCR to measured erbB-2 expression levels in mouse fibroblast cells, cell lines derived from canine osteogenic sarcomas and canine OSA samples. Our results show that erbB-2 was significantly overexpressed in 86% (6/7) of the OSA cell lines and 40% (4/10) of the OSA tissues samples. Moreover, immunohistochemical (IHC) analysis of HER-2 shows that indeed gene expression patters for erbB-2 are consistent with subsequent expression of functional HER-2, thus further implicating canine HER-2/erbB-2 as a possible therapeutic target. To further substantiate the prognostic value of erbB-2 overexpression, longevity following diagnosis was collected for the ten clinical cases described in this study. Analysis of these data shows that overexpression of erbB-2 decreases longevity by 115.5 days. These data demonstrate that overexpression of HER-2/erbB-2 is detected in a significant percentage of canine OSA; thereby lending credence to the fact that HER-2/erbB-2 may indeed be an important prognostic indicator and therapeutic target for the initial diagnosis and treatment of canine OSA. In conclusion, our results closely follow other studies in which HER-2 overexpression in human OSA patients was an indicator of poor prognosis.
J Vet Intern Med. 2003 Mar-Apr;17(2):199-205. :
Carboplatin and doxorubicin combination chemotherapy for the treatment of appendicular osteosarcoma in the dog.
Bailey D, Erb H, Williams L, Ruslander D, Hauck M.
Department of Clinical Sciences, North Carolina State University, Raleigh, NC 27606, USA.

Twenty-four client-owned dogs with histologically diagnosed appendicular osteosarcoma (OSA) and no evidence of gross metastatic disease were treated with amputation or limb salvage followed by combination chemotherapy consisting of carboplatin (175mg/ m2 IV, day 1) and doxorubicin (15 mg/m2 IV, day 2) given on a 21-day cycle for a maximum of 4 cycles. Hematologic and gastrointestinal adverse effects were graded according to National Cancer Institute guidelines. Thoracic radiographs were obtained before the 3rd chemotherapy cycle and then every 2 months. Median disease-free interval was 195 days (95% confidence interval 111-228 days) and median survival was 235 days (95% confidence interval 150-283 days). Two patients required dose reductions: 1 for grade 3 thrombocytopenia and 1 for grade 3 adverse gastrointestinal effects. Patients with a longer duration of clinical signs before definitive diagnosis and surgery (greater than 30 days) were more likely to develop progressive disease and to die or be euthanized because of progressive disease on any day; hazard ratios were 3.0 (P = .02) and 3.7 (P .02), respectively. In conclusion, although this combination chemotherapy protocol was well tolerated, it did not provide any improvement over historical single-agent protocols.

I got as much cottage cheese as I wanted. She was smart enough to mix the flaxseed
oil(Barleans high in lignans) in so it didn't separate..I couldn't taste
the Ip-6, the echincea with goldenseal, the astragalus, the pau d'arco, the
vitamin e, the coenzyme q 10 for my circulation and as antioxidant, the odorless garlic, and
whatever.

She actually started calling me "The Flaxseed Kid"..The more
she read about flaxseed the more she was convinced that that and my strong
will was why I was still with her. If you read the abstracts(she wants you to)you
will see why..who knows maybe it did help protect my liver, my heart, help
my good old neurotransmitters transmit, help my joints, help overall with
inflammation..I am just or was just a dog..go by the abstracts.. She finally
added olive leaf extract and sometimes threw in sardines and fish oil. She would also like you to check out more on grapes...more abstracts to make you a believer..Proanthocyanidins and resveratrol. She also added milk thistle and LiverCare. She didn't add SAMe or melatonin but kicked herself later for not adding them or NAC. She did try Essiac but I couldn't acquire a taste for that bitter stuff. Bromelain
wasn't bad. Only on rare occasions did she give me red meat because she read
that red meat and cancer wasn't good. Yes I got brown rice and millet and
oatmeal. Helped me to poop. I got a lot of chicken..All cooked. I was never
big on vegetables..We schnauzers have sensitive stomachs...
The next year I didn't need to sleep that much. I was able to always hold
my head high..yes it is a dog thing...and I could enjoy surprising my companion
with how well I could get along on the three legs. I gave her warnings
towards the end that I was getting tired and was getting ready to take my
leave. She was horrified me to find me in the cat's litterbox...She thought
I was perfect and felt it was a travesty to be found in the box..Only later
did she understand that the litter was the only natural place in apartment
to rest..She began cutting down on the supplements..I think she was getting
clues from me that I was tired and that I wanted to take my leave with the
dignity I thought I was entitled to. Humans just don't have the same stoicism
as dogs and cats have. We aren't afraid of death or dying..It is so natural
to us..We are afraid for our companions and if they can handle our not being
physically present. See we too are forced to make decisions.

Thank goodness we are not expected to talk or hold hands or keep promises. We simply rely on the power of love.

I
was getting worried about my brother Hammy. He and my wiring were quite different.
He handled my cancer with dignity but aloofness.

Hammy has always been a very proud alpha dog. As soon as I started limping, he started avoiding me, even in the small space we lived in. He never showed signs of jealousy except once over food. Then we got into a tussle and Bobby was horrified he would break my leg. Finally, in the last year, he let me groom him again. I used to always clean his privates. I took care of Hammy as I took care of Bobby. He pretended I wasn't there but let me clean him. He also let me take the lead and set the pace on our walks.

The last month of my life he knew I was leaving. Whenever Bobby would leave, he would howl until she returned. It was as if I weren't there anymore. I understood. He didn't understand that now it was his turn to be numero uno and only physical dog in the household. For two and half years, he graciously took back seat. Now he would control the show and once again set the pace and get all the treats and be the center. He was astonishingly wonderful about the
whole thing until afterwards. He let his grief turn inward. Dogs don't blame
like humans. He just became lost. He assumed I would always be with him..He
still doesn't know I am and plan to resume the play fighting when he rejoins
me in that oneness.Bobby did a webpage about Hammy and his separation anxiety and grieving and the remedies she has used. Please click here if you want some suggestions for doggies' four legged companions who are also grieving.I
was getting prepared for my journey. She found me early in on a friday morning,
peacefully stretched out near the litterbox..I had tried to make it into
the box but I was just way too tired... guess for her sake, best I hadn't
made it. She should know that love always wins and that pain slowly evaporates.
She lights many candles not so much in memory of me but to know that I am
forever with her...she can't touch me anymore..same as she can't touch the
flame...if she tries to get too close she will feel pain..but if she gets
close enough she feels my warmth...but the beauty of the dancing flames speaks
volumes of the love that flows..no longer do our bodies separate from each
other..I have become part of the one which she and my brother will join when
it is their time...

*

I am happy to say my companion just celebrated the anniversary of my death..She
didn't mourn my loss but celebrated my life and laughed and really enjoyed
the day with a close friend. She first lit a candle and watched it for a
half an hour. It wasn't a solemn occasion but rather some sort of connection
that helped reinforce that I was no longer in my earthly form but still just
as close to her but if she tried to cling too closely she would feel the
pain as if it were yesterday. I was glad that she forgot finally about the
cancer and just focussed on all the fun memories and my delightful personality
and pranks and trademarks during the rest of the day. I also teased her during
the day and I think she knew it. I am so glad she didn't mop and mourn and
waste time ..there is a time for mourning and a time for healing and a time
for rememberance...and of course a time for CELEBRATING-WE HAD SO MUCH FUN
ON EARTH TOGETHER AND THAT SURELY COUNTSIt has been over a year and a half since Morgy became a tough little angel. Yes the pain has dulled a bit but the longing to be with him has no. Somebody told me it takes four years for the pain to go away and that the sense of loss never goes away. There will always be tears and the most beautiful memories mixed with the tears.On September 18, 2003 my brother Hammy joined me. I had been sending messages to my companion Bobby for two months that I wanted Hammy to be with me but she was still left in shock. Hammy died nobly and with dignity. He was put to sleep because his kidneys were giving out and he was suffering from severe nausea with dry heaving and loss of appetite and diarrhea. Now two of the pack on this side are together again. We are patiently awaiting our companion Bobby to join us

My companion wishes this article came out while I was on earth-she has read a lot about melatonin but this research abstract says a lot. Melatonin also one of the cheaper supplements.

RIMADYL-About RimadySigns
of Rimadyl intolerance may include appetite loss, vomiting and diarrhea,
which could indicate rare but serious side effects
involving the digestive tract, liver or kidneys. If these signs occur, discontinue
Rimadyl therapy and contact your veterinarian.
For additional product details, including drug
interaction information"

natural natural cortisol-click here"he importance of dosing ranges is so very evident especially when distinguishing between natural and synthetic glucocorticoids. Prednisone, cortisone, dexamethasone and the like are certainly no exception. It also must be attributable to clinical studies using amounts in excess of physiologic requirements. Eventually, it was thought that any patient (human or animal) who received cortisone therapy was thought to be in jeopardy - regardless of the possiblility that smaller doses might have been safer and just as effective.""Calcium depletion is another factor in long-term or elevated synthetic steroid use. This process of depletion can be a contributor to congestive heart failure and circulatory deficiencies. Liver enzyme elevation is another common response to long-term synthetic corticolteroid use. Elevated aspartate transaminase (SGOT) and alanine transaminase (SGPT) serve as markers for the onset of liver disease, toxic hepatitis, infectious mononucleosis, pancreatitis, hepatocellular disease and active cirrhosis. These conditions have all been seen with long-term or elevated doses of the synthetic steroids."

Paclitaxel (Taxol) was administered to 25 dogs with histologically confirmed malignant tumors at a dosage of 165 mg/m2 i.v. over 3-6 hours every 3 weeks. Dogs received premedication with antihistimines and corticosteroids to reduce hypersensitivity reactions. However, 64% of the dogs still experienced allergic reactions. Six dogs (24%) had grade 3 or 4 neutropenia, 6 dogs (24%) required hospitalization and 3 dogs (12%) died of sepsis. Five dogs (20%) had a partial response (osteosarcoma [2 dogs] mammary carcinoma [2 dogs] and malignant histiocytosis [1 dog]) for a median duration of 53 days. The overall toxicity was unacceptable at the 165 mg/m2 dose. Therefore, subsequent evaluations of paclitaxel in tumor-bearing dogs should a starting dose of 132 mg/m2 i.v. every 3 weeks.

Vet Parasitol. 2004 Jan 30;119(2-3):209-21. :
Spirocercosis-associated esophageal sarcomas in dogs. A retrospective study of 17 cases (1997-2003).
Ranen E, Lavy E, Aizenberg I, Perl S, Harrus S.
School of Veterinary Medicine, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel. ranen@agri.huji.ac.il
Seventeen client-owned dogs diagnosed with spirocercosis-associated esophageal sarcomas were retrospectively reviewed. The most common clinical signs noticed were vomiting and/or regurgitation (94%), lethargy and depression (59%), pyrexia and anorexia (41% each). Leukocytosis (82%) and microcytic hypochromic anemia (30%) were the most common hematological abnormalities. Caudal thoracic masses were demonstrated on survey radiographs of 13/15 of the dogs and thoracic spondylitis was detected in 12/15 dogs. Spirocerca lupi eggs were detected in 2/8 patients and worms were demonstrated on 1/11 at necropsy. Ten cases underwent surgical attempt to remove the tumors. In six of them partial esophagectomy (PE) was performed and all of them survived the immediate postoperative hospitalization. Five of the cases that underwent PE also received chemotherapy after surgery (doxorubicin (Adriamycin, Upjohn)) with an average survival time of 267 days. The histopathological results of the esophageal tumors were osteosarcoma (9), fibrosarcoma (5) and undifferentiated sarcoma (1). In areas endemic to spirocercosis, regurgitation or vomiting in dogs and microcytic hypochromic anemia and neutrophilia warrant ruling out esophageal sarcomas. Proper surgical treatment could prolong the dogs' lifespan for months, and improve their quality of life.

Vet Surg. 2003 Nov-Dec;32(6):539-44. :
Pasteurized tumoral autograft and adjuvant chemotherapy for the treatment of canine distal radial osteosarcoma: 13 cases.
Morello E, Vasconi E, Martano M, Peirone B, Buracco P.
Dipartimento di Patologia Animale, School of Veterinary Medicine, Turin, Italy.
OBJECTIVE: To report outcome in 13 dogs with distal radial osteosarcoma, without evidence of metastasis, treated by a combination of adjuvant chemotherapy and a pasteurized autograft limb-sparing procedure. STUDY DESIGN: Prospective clinical study. ANIMALS: Thirteen dogs with distal radial osteosarcoma. METHODS: Limb-sparing procedure was performed using an autograft from the excised tumoral segment, pasteurized at 65 degrees C for 40 minutes. Adjuvant chemotherapy (cisplatin or cisplatin and doxorubicin) was administered in all dogs. RESULTS: Mean and median survival times were 531 and 324 days, respectively (range, 180 to 1,868 days). Overall survival was 100% at 6 months, 50% at 12 months, 44% at 18 months, and 22% at 24 months. Lung metastasis occurred in 5 (38%) dogs. Observed complications were local recurrence (2 dogs, 15%), allograft infection (4 dogs, 31%), and implant failure (3 dogs, 23%). Limb function was good in 12 dogs (92%) and fair in 1 dog. CONCLUSIONS: Pasteurized bone autograft derived from the tumoral bone segment was an effective alternative to cortical bone allograft for limb sparing in canine distal radial osteosarcoma, in terms of feasibility, pattern of healing, complications, and survival. CLINICAL RELEVANCE: Use of a pasteurized bone autograft eliminates the need for a canine bone allograft bank and has the added advantage of good fit to the recipient site. Copyright 2003 by The American College of Veterinary Surgeons
Cancer Res 2002 Jan 15;62(2):356-8
:
Effects of the cyclooxygenase inhibitor, piroxicam, on tumor
response, apoptosis, and angiogenesis in a canine model of human
invasive urinary bladder cancer.
Mohammed SI, Bennett PF, Craig BA, Glickman NW, Mutsaers AJ,
Snyder PW, Widmer WR, DeGortari AE, Bonney PL, Knapp DW.
Department of Veterinary Clinical Sciences, Purdue University, West
Lafayette, Indiana 47907, USA.The mechanisms by which cyclooxygenase inhibitors exert antitumor effects are
not completely defined but are postulated to involve antiangiogenic effects and
induction of apoptosis. In this study, we determined the effects of the cox
inhibitor, piroxicam, on tumor response, apoptotic index, proliferative index,
cyclooxygenase-2 expression, prostaglandin E(2) concentration, tumor
microvessel density, and urine basic fibroblast growth factor and vascular
endothelial growth factor concentrations in pet dogs with naturally occurring
invasive transitional cell carcinoma of the urinary bladder. Piroxicam caused
reduction in tumor volume in 12 of 18 dogs, and this was strongly associated
with induction of apoptosis (Fisher's exact test P < 0.015) and reduction in
urine basic fibroblast growth factor concentration.Eur J Clin Nutr 1999 Oct;53(10):764-70 :
Coenzyme Q10 in health and disease.
Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S.
The Danish Nutrition Council, Soborg, Denmark.
The literature concerning the importance of coenzyme Q10 in health
and disease has been reviewed. Usual dietary intake together with normal
in vivo synthesis seems to fulfil the demands for Q10 in healthy individuals.
The importance of Q10 supplementation for general health has not been investigated
in controlled experiments. The literature allows no firm conclusions about
the significance of Q10 in physical activity. In different cardiovascular
diseases, including cardiomyopathy, relatively low levels of Q10 in myocardial
tissue have been reported. Positive clinical and haemodynamic effects of
oral Q10 supplementation have been observed in double-blind trials, especially
in chronic heart failure. These effects should be further examined. No important
adverse effects have been reported from experiments using daily supplements
of up to 200 mg Q10 for 6-12 months and 100 mg daily for up to 6 y. J Cardiovasc Nurs 2002 Jul;16(4):9-20;
Coenzyme Q10 and cardiovascular disease: a review.
Sarter B.
Department of Nursing, University of Southern California, Los Angeles, California, USA.
This article provides a comprehensive review of 30 years of research
on the use of coenzyme Q10 in prevention and treatment of cardiovascular
disease. This endogenous antioxidant has potential for use in prevention
and treatment of cardiovascular disease, particularly hypertension, hyperlipidemia,
coronary artery disease, and heart failure. It appears that levels of coenzyme
Q10 are decreased during therapy with HMG-CoA reductase inhibitors, gemfibrozil,
Adriamycin, and certain beta blockers. Further clinical trials are warranted,
but because of its low toxicity it may be appropriate to recommend coenzyme
Q10 to select patients as an adjunct to conventional treatment. J Card Fail 2000 Sep;6(3):233-42 :
The role of coenzyme Q10 in the pathophysiology and therapy of experimental congestive heart failure in the dog.
Harker-Murray AK, Tajik AJ, Ishikura F, Meyer D, Burnett JC, Redfield MM.
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
BACKGROUND: Coenzyme Q10 (CoQ10) is essential for ATP generation
and has antioxidant properties. Decreased CoQ10 levels have been reported
in human heart failure (CHF), but it remains unclear if this is a conserved
feature of CHF. The objective of the study was to determine if tachycardia-induced
CHF in the dog is associated with reduced CoQ10 levels. Furthermore, it was
hypothesized that CoQ10 supplementation may improve CHF severity by preventing
CoQ10 deficiency (if present) or via antioxidant effects. Methods and Results:
Serum and myocardial levels of CoQ10 were examined in normal dogs (n = 6),
dogs with CHF (control, n = 5), and dogs with CHF treated with CoQ10 (CoQ10;
10 mg/kg/day, n = 5). Serum CoQ10 levels did not change with CHF in control
dogs, and myocardial levels were similar to those of normal dogs. CoQ10 therapy
increased serum but not myocardial levels of CoQ10. In early CHF, CoQ10-treated
dogs had lower filling pressures, and, in severe CHF, CoQ10-treated dogs
had less hypertrophy as compared with untreated dogs. Other indices of CHF
severity were similar in control and CoQ10-treated dogs. Conclusion: These
data indicate that CoQ10 deficiency is not present in this model of CHF.
Although dramatic effects on hemodynamics were not observed, CoQ10 supplementation
did appear to attenuate the hypertrophic response associated with CHF. Key
words: enzymes, cardiomyopathy, hormones, antioxidant.
J Gastroenterol 1996 Jun;31(3):379-86 : Pathophysiological effect of hepatic
ischemia and reperfusion after hepatectomy in dogs with obstructive jaundice,
focusing on the effect of coenzyme Q10 and styrene-co-maleic acid superoxide
dismutase.
Ogura Y, Takagi K, Kawarada Y, Mizumoto R.
First Department of Surgery, Mie University School of Medicine, Japan.
The purpose of the present study was to elucidate the effect of hepatic
reflow following ischemia on the remnant liver after hepatectomy with occluded
hepatic blood inflow in dogs with obstructive jaundice. When 40% hepatectomy
was performed with 10-min occlusion of hepatic blood inflow in dogs with
obstructive jaundice, the lipid peroxide content in the remnant liver increased
significantly, together with a reduction in superoxide dismutase (SOD)-like
activity. The levels of endotoxin and beta-N-acetyl hexosaminase (NAH) in
peripheral blood also increased. The phagocytic index increased transiently
after 30 min, followed by a marked decrease after 3h. Histologically, degeneration
and necrosis of the hepatic parenchymal cells were demonstrated, and survival
rate at 7 days was only 23.1%. With the administration of coenzyme Q10 (CoQ10)
or styrene-co-maleic acid SOD (SM-SOD), these phenomena were significantly
inhibited, and the survival rate improved. After hepatectomy, Kupffer cells
in the remnant liver were activated by increased endotoxin levels in the
portal vein, inducing the production of free radicals, which, in turn, damaged
the Kupffer cells by reducing endotoxin clearance. Finally, the impaired
functional reserve in the remnant liver provoked liver failure. The administration
of CoQ10 or SM-SOD prevented the occurrence of these phenomena triggered
by the free radicals generated by Kupffer cells, stimulated by endotoxin
in the portal vein. Haemostasis 1996 Jan-Feb;26(1):38-44 :
Plasma serotonin and platelet aggregation during ischemia-reperfusion in dogs: effect of dipyridamole and coenzyme Q10.
Choudhury NA, Malyszko J, Ahmed MH, Pietraszek MH, Nakamura S, Nakai K, Rashid MA, Takada A, Baba S.
Second Department of Surgery, Hamamatsu University School of Medicine, Japan.
Platelet aggregation and plasma serotonin were studied during ischemia-reperfusion
of the small intestine in dogs. Blood was withdrawn from the superior mesenteric
vein before and 1 h after ischemia, then 5, 30 and 60 min after reperfusion.
Dipyridamole (5 mg/kg body weight) and coenzyme Q10 (CoQ10; 10 mg/kg body
weight) were administered intravenously 5 min before reperfusion, following
1 h ischemia, in order to investigate their effects on platelet function
and free serotonin. Ischemia-reperfusion resulted in an increased local free
serotonin concentration together with an enhanced platelet response to ADP,
collagen and arachidonic acid. Administration of dipyridamole and CoQ10 prior
to reperfusion prevented, at least in part, augmented platelet activation
and serotonin release. It appeared that dipyridamole was more potent than
CoQ10. Our results may indicate a possible protective effect of dipyridamole
on enhanced platelet activation during ischemia-reperfusion in dogs. J Am Coll Nutr 2003 Apr;22(2):118-23 :
The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer.
Drisko JA, Chapman J, Hunter VJ.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology
(J.C., V.J.H.), University of Kansas Medical Center, Kansas City, Kansas.
OBJECTIVE: Because of poor overall survival in advanced ovarian
malignancies, patients often turn to alternative therapies despite controversy
surrounding their use. Currently, the majority of cancer patients combine
some form of complementary and alternative medicine with conventional therapies.
Of these therapies, antioxidants, added to chemotherapy, are a frequent choice.
METHODS: For this preliminary report, two patients with advanced epithelial
ovarian cancer were studied. One patient had Stage IIIC papillary serous
adenocarcinoma, and the other had Stage IIIC mixed papillary serous and seromucinous
adenocarcinoma. Both patients were optimally cytoreduced prior to first-line
carboplatinum/paclitaxel chemotherapy. Patient 2 had a delay in initiation
of chemotherapy secondary to co-morbid conditions and had evidence for progression
of disease prior to institution of therapy. Patient 1 began oral high-dose
antioxidant therapy during her first month of therapy. This consisted of
oral vitamin C, vitamin E, beta-carotene, coenzyme Q-10 and a multivitamin/mineral
complex. In addition to the oral antioxidant therapy, patient 1 added parenteral
ascorbic acid at a total dose of 60 grams given twice weekly at the end of
her chemotherapy and prior to consolidation paclitaxel chemotherapy. Patient
2 added oral antioxidants just prior to beginning chemotherapy, including vitamin C, beta-carotene, vitamin E, coenzyme Q-10 and a multivitamin/mineral complex. Patient
2 received six cycles of paclitaxel/carboplatinum chemotherapy and refused
consolidation chemotherapy despite radiographic evidence of persistent disease.
Instead, she elected to add intravenous ascorbic acid at 60 grams twice weekly.
Both patients gave written consent for the use of their records in this report.
RESULTS: Patient 1 had normalization of her CA-125 after the first cycle
of chemotherapy and has remained normal, almost 3(1/2) years after diagnosis.
CT scans of the abdomen and pelvis remain without evidence of recurrence.
Patient 2 had normalization of her CA-125 after the first cycle of chemotherapy.
After her first round of chemotherapy, the patient was noted to have residual
disease in the pelvis. She declined further chemotherapy and added intravenous
ascorbic acid. There is no evidence for recurrent disease by physical examination,
and her CA-125 has remained normal three years after diagnosis. CONCLUSION:
Antioxidants, when added adjunctively, to first-line chemotherapy, may improve
the efficacy of chemotherapy and may prove to be safe. A review of four common
antioxidants follows. Because of the positive results found in these two
patients, a randomized controlled trial is now underway at the University
of Kansas Medical Center evaluating safety and efficacy of antioxidants when
added to chemotherapy in newly diagnosed ovarian cancer. J Am Vet Med Assoc 2001 Jun 1;218(11):1783-6
:
Evaluation of piroxicam for the treatment of oral squamous cell
carcinoma in dogs.
Schmidt BR, Glickman NW, DeNicola DB, de Gortari AE, Knapp DW.
Department of Veterinary Clinical Sciences, School of Veterinary Medicine,
Purdue University, West Lafayette, IN 47907, USA.OBJECTIVE: To evaluate the use of piroxicam for the treatment of oral
squamous cell carcinoma in dogs. DESIGN: Prospective case series. ANIMALS:
17 dogs with measurable oral squamous cell carcinoma. PROCEDURE: Dogs were
treated with piroxicam at a dosage of 0.3 mg/kg (0.14 mg/lb) of body weight,
PO, every 24 hours until progressive disease or unacceptable signs of toxicosis
developed or the dog died. RESULTS: One dog had a complete remission
(maxillary tumor), and 2 dogs had partial remissions (lingual tumor and tonsillar
tumor). An additional 5 dogs had stable disease, including 1 with a maxillary
tumor, 2 with mandibular tumors, and 2 with tonsillar tumors. Variables
associated with tumor response were not identified. Median and mean times to
failure for the 3 dogs that had a remission were 180 and 223 days,
respectively. Median and mean times to failure for the 5 dogs with stable
disease were 102 and 223 days, respectively. Time to failure was positively
associated with tumor response and negatively associated with tumor size. One
dog had mild adverse gastrointestinal tract effects that resolved with the
addition of misoprostol to the treatment regimen. CONCLUSIONS AND
CLINICAL RELEVANCE: Results suggest that piroxicam may be useful in the
treatment of dogs with oral squamous cell carcinoma; response rate was similar
to that reported for other cytotoxic treatments. Larger-scale studies are
warranted to determine what role piroxicam may have, alone or in combination
with other treatments, for the treatment of dogs with oral squamous cell
carcinoma.

TORBUTROL-opioid antitussive drug

fentanyl transdermal patch

Am J Vet Res 1996 May;57(5):715-9
:
Disposition of transdermally administered fentanyl in dogs.
Kyles AE, Papich M, Hardie EM.
Department of Companion Animal and Special Species Medicine, College of
Veterinary Medicine, North Carolina State University, Raleigh 27606, USA.OBJECTIVE--To evaluate the disposition of fentanyl after i.v. and transdermal
administrations. The hypothesis was that transdermal administration of fentanyl
would result in a measurable plasma opioid concentration. DESIGN--Each dog
received 2 treatments in a randomized, crossover design. ANIMALS--6 clinically
normal Beagles. PROCEDURE--2 treatments consisting of i.v. fentanyl (50
micrograms/kg of body weight) and transdermal fentanyl (50 micrograms/h)
administrations. Plasma fentanyl concentrations were measured at fixed times, and
pharmacokinetic values were calculated. RESULTS--Intravenous pharmacokinetics
of fentanyl was similar to those previously described in dogs and provided the
distribution and clearance data necessary to calculate the rate of absorption of the
transdermally administered opioid. The transdermal fentanyl patch produced
average steady-state concentrations of 1.6 ng/ml. The actual rate of delivery of
transdermal fentanyl was 35.7 (range, 13.7 to 49.8) micrograms/h, which
represented 71.48% (range, 27.45 to 99.56%) of the theoretical rate of delivery.
The mean elimination half-life of fentanyl after patch removal was 1.39 hours.
CONCLUSIONS--Transdermally administered fentanyl resulted in fairly constant
plasma concentrations, in the range generally considered to be analgesic, from 24 to
72 hours after application of the patch. The rate of drug delivery was less than
expected, and there was substantial individual variation. CLINICAL
RELEVANCE--Transdermally administered fentanyl has the potential to be a
clinically useful analgesic regimen in dogs, and further evaluation of its analgesic
actions and potential side effects warrantedVet Surg 1998 Mar-Apr;27(2):159-66
:
Comparison of plasma fentanyl concentrations by using three
transdermal fentanyl patch sizes in dogs.
Egger CM, Duke T, Archer J, Cribb PH.
Department of Anesthesiology, Radiology and Surgery, Western College of
Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada.OBJECTIVE: To compare plasma fentanyl concentrations attained after the
application of three transdermal fentanyl patch sizes (50, 75, and 100
micrograms/hour) in dogs. DESIGN: Repeated Latin square controlled study.
ANIMALS: Six intact, mixed-breed adult dogs (2 males, 4 females) weighing 19.9 +/-
3.4 kg. METHODS: Each dog was randomly assigned to receive each of three
treatments: 50 (P50), 75 (P75), or 100 (P100) micrograms/hour transdermal
patches. Patches were left in place for 72 hours. Jugular venous blood was collected
at 1, 2, 4, 8, 12, 24, 36, 48, 60, and 72 hours after patch application and for 1, 2, 4,
8, and 12 hours after patch removal. Plasma fentanyl concentrations were measured
using a radioimmunoassay technique. After a 96-hour washout period, each dog was
moved to another treatment group and received a different patch size. RESULTS:
The following results were obtained (mean +/- SD): average plasma fentanyl
concentration from 24 to 72 hours, 0.7 +/- 0.2 ng/mL (P50), 1.4 +/- 0.5 ng/mL (P75),
1.2 +/- 0.5 ng/mL (P100); the total area under the concentration versus time curve (0
hours to infinity), 46 +/- 12.2 ng/h/mL (P50), 101.2 +/- 41.4 ng/h/mL (P75), 80.4 +/-
38.3 ng/h/mL (P100); and the apparent elimination half-life, 3.6 +/- 1.2 hours (P50),
3.4 +/- 2.7 hours (P75), and 2.5 +/- 2.0 hours (P100). There was a high degree of
variability in plasma fentanyl concentrations achieved. Plasma fentanyl
concentrations declined rapidly after patch removal. CONCLUSIONS: The
attainment of steady-state plasma concentrations takes up to 24 hours, and there is
a great deal of variability in the final concentrations reached in different
individuals. In this study, the 100 micrograms/hour patches did not provide
statistically increased plasma concentrations when compared with the 50
micrograms/hour patches. CLINICAL RELEVANCE: Because of the interindividual
and intraindividual variation in plasma fentanyl concentrations, patches should be
applied 24 hours before the anticipated time that analgesia will be required.
Adequacy of analgesia and potentially deleterious side effects, such as sedation and
respiratory depression, should be monitored while the patches are in place. Skin
reactions may occur, and the patches should be removed if such skin irritation is
seen. After the patch is removed, it is expected that analgesia will wane rapidly
because of the brief elimination half-life.J Am Anim Hosp Assoc 1999 Mar-Apr;35(2):95-100
:
A comparison of transdermal fentanyl versus epidural morphine
for analgesia in dogs undergoing major orthopedic surgery.
Robinson TM, Kruse-Elliott KT, Markel MD, Pluhar GE, Massa K, Bjorling DE.
Department of Surgical Sciences, School of Veterinary Medicine, University of
Wisconsin, Madison 53706-1102, USA.Postoperative analgesia provided by transdermal fentanyl was compared with that
provided by epidural morphine in dogs undergoing major orthopedic surgery. Dogs
randomly were assigned to receive either a 100 microg per hour transdermal
fentanyl patch 24 hours prior to surgery (n=8) or epidural morphine (0.1 mg/kg body
weight) administered following induction of anesthesia (n=10). Temperature, heart
rate, respiratory rate, and pain score were recorded prior to surgery and zero, six,
18, 30, and 42 hours after surgery. Blood samples were collected from the dogs in
the transdermal fentanyl group beginning 24 hours preoperatively to 42 hours
postoperatively. Fentanyl concentrations were determined by radioimmunoassay.
When all time periods after surgery were combined, dogs in the transdermal
fentanyl group were experiencing significantly less pain after surgery than dogs
given epidural morphine. The transdermal fentanyl provided analgesia after major
orthopedic surgery greater than or equivalent to that of epidural morphine.DeramaxxDeramaxx"The
First and Only Coxib Class Drug Approved for Dogs. Bullseye!This breakthrough
chemistry uniquely targets the COX-2 enzyme to control pain.Thus, DERAMAXX
is designed to spare the COX-1 enzyme responsible for normal platelet function
and gastric protection. DERAMAXX is also the only drug approved by the
FDA* for the control of postoperative orthopedic pain and inflammation
in dogs. So now when your canine patients need pain control after orthopedic
surgery, you can always be on target."vetlearn forumt would be nice if this were the case, but a simple search on Medline will show that Celebrex from
which Deramaxx was derived is metabolized differently by dogs with a particular genetic variation. In
some dogs, this means that Celebrex accumulates to toxic levels. In the very short term testing done
in support of the application to the FDA for Deramaxx, this same behavior was noted with Deramaxx
and it is noted on the FDA-approved label.
It is possible that Deramaxx does not metabolized in the same way as Celebrex. It differs from
Celebrex by one atom and it is structurally different. But at this stage, given what is well known and
well documented in the scientific literature about Celebrex and dogs, I think there is every reason to
be cautious with respect to Deramaxx until this issue is cleared up. Further, Deramaxx has only
been approved for SHORT term postop use.
Prednisone-for pain by reducing swelling..the studies below help illustrate
that it also lowers immune system...immune system fights the cancer :-(Prednisone & prednsolone Anti-inflammatory (especially for joint pain and itchy skin)
Shock (steroids seem to help improve circulation)
Cancer Chemotherapy (especially in the treatment of lymphoma)
Prednisone & prednsolone have activity in the kidney leading to the
conservation of salt. This creates the classical side effects of
prednisone/prednisolone use: excessive thirst and excessive urination. If
this occurs, another steroid can be selected or the predisone/prednisolone
dose can be dropped.Any latent infections can be unmasked by prednisone use. (Feline upper
respiratory infections would be a classical example. When a cat recovers
clinically, the infection simply goes dormant. Glucocorticoid use could bring
the infection out again.)
Can J Vet Res 1999 Jan;63(1):18-24
:
The effects of prednisone and azathioprine on circulating
immunoglobulin levels and lymphocyte subpopulations in normal
dogs.
Rinkardt NE, Kruth SA, Kaushik A.
Department of Clinical Studies, University of Guelph, Ontario.This study investigates serum immunoglobulin (SIg) levels and lymphocyte
subpopulations in normal dogs in response to putative immunosuppressive doses
of prednisone and/or azathioprine. The objectives were to quantify SIg levels
and lymphocyte subpopulations, including Thy-1+, CD4+, CD8+ and B cells, in
normal dogs both before and after the administration of prednisone and/or
azathioprine at 2 mg/kg, PO, each. Eighteen beagles were divided into 3 groups
of 6 dogs each. Blood samples for radial immunodiffusion assay of IgG, IgM and
IgA, complete blood count (CBC)and flow cytometry were collected prior to the
administration of any drugs and again after 14 d of azathioprine, prednisone or
azathioprine and prednisone. Peripheral blood mononuclear cells were isolated
using density centrifugation and were incubated with monoclonal antibodies
reacting with CD4+, CD8+, Thy-1+ and membrane immunoglobulin. Lymphocyte
subsets were quantified using flow cytometry. Azathioprine-treated dogs had
no significant changes in SIg levels or lymphocyte subpopulations.
Prednisone-treated dogs had significant (P < 0.05) decreases in all SIg levels,
all lymphocyte subpopulations and erythrocyte numbers, and had an increase in
neutrophil counts. Prednisone and azathioprine-treated dogs had significant (P <
0.05) decreases in serum IgG levels and Thy-1+ and CD8+ lymphocyte
subpopulations, with an increase in the CD4:CD8. These dogs also had a
significant decrease in erythrocyte number and a significant increase in the
monocyte count. These findings suggest that azathioprine and prednisone in
combination or prednisone alone may be useful for the treatment of T
cell-mediated diseases since decreased circulating T cell levels were
demonstrated following treatment. The combination of drugs or azathioprine
alone may not be appropriate for treatment of acute or autoantibody-mediated
immune disease, because SIg levels were minimally affected by treatment.J Am Vet Med Assoc 2002 Feb 15;220(4):477-81
:
Comparison of platelet count recovery with use of vincristine and
prednisone or prednisone alone for treatment for severe
immune-mediated thrombocytopenia in dogs.
Rozanski EA, Callan MB, Hughes D, Sanders N, Giger U.
Department of Clinical Studies, School of Veterinary Medicine, University of
Pennsylvania, Philadelphia 19104-6010, USA.OBJECTIVE: To evaluate the effect of prednisone alone, compared with a
combination of prednisone and vincristine, on platelet counts in bleeding dogs
with severe primary immune-mediated thrombocytopenia (IMT). DESIGN:
Prospective case study. ANIMALS: 24 dogs with severe primary IMT
PROCEDURE: All dogs received immunosuppressive doses of prednisone (1.5 to
2 mg/kg [0.7 to 0.9 mg/lb] of body weight, PO, q 12 h). In addition, 12 dogs
received a single dose of vincristine (0.02 mg/kg [0.01 mg/lb], IV). Platelet
count, transfusion requirement, and outcome were monitored. A response was
defined as an increase in platelet count to > or = 40,000/microl. Dogs in the
prednisone group that failed to respond received 1 dose of vincristine on day 7.
RESULTS: Dogs that received prednisone and vincristine had a significantly
faster increase in platelet count to > or = 40,000 platelets/microl than dogs
that received prednisone alone (mean +/- SD, 4.9 +/- 1.1 vs 6.8 +/- 4.5 days,
respectively). A similarly rapid response was observed in dogs that received
vincristine on day 7 after treatment with prednisone alone failed. Furthermore,
duration of hospitalization was reduced in the vincristine group, compared with
the prednisone group (5.4 +/- 0.3 vs 7.3 +/- 0.5 days, respectively). No
adverse effects attributable to vincristine were observed in any dog.
CONCLUSIONS AND CLINICAL RELEVANCE: Administration of combined
vincristine and prednisone is associated with more rapid increase in platelet
numbers and shortened duration of hospitalization in dogs with IMT, compared
with use of prednisone alone. Early use of vincristine seems warranted in dogs
with severe primary IMT.

REGLAN-Metoclopramide

CYTOTEC-Misoprostol-FOR GASTRIC SIDE EFFECTS
J Clin Pharm Ther 1991 Dec;16(6):385-409
:
Misoprostol--a logical therapeutic approach to gastroduodenal
mucosal injury induced by non-steroidal anti-inflammatory drugs?
Fenn GC, Robinson GC.
Medical Department, G. D. Searle & Co. Ltd, High Wycombe, Bucks, U.K.Misoprostol is a synthetic analogue of naturally occurring prostaglandin E1. The
basis of the damaging actions of non-steroidal anti-inflammatory drugs
(NSAIDs) on the gastrointestinal (GI) tract is believed to be a consequence of
two events: a direct damaging action on mucosal integrity and depletion of
endogenous mucosal prostaglandins (PGs). Due to the latter effect, and because
current evidence indicates that PGs play an important role in maintaining the
integrity of the GI tract, misoprostol has been developed as a logical therapy
to prevent and heal gastric and duodenal damage caused by NSAIDs. The
purpose of this review is to consider the need for such a therapy, to describe
its pharmaceutical development, to review its pharmacology and to review its
efficacy compared with other available agents.J Am Coll Surg 1998 Sep;187(3):276-86
:
Attenuation of ischemic liver injury by prostaglandin E1 analogue,
misoprostol, and prostaglandin I2 analogue, OP-41483.
Totsuka E, Todo S, Zhu Y, Ishizaki N, Kawashima Y, Jin MB, Urakami A,
Shimamura T, Starzl TE.OI H
Thomas E Starzl Transplantation Institute, University of Pittsburgh, PA
15213-2582, USA.BACKGROUND: Prostaglandin has been reported to have protective effects
against liver injury. Use of this agent in clinical settings, however, is limited
because of drug-related side effects. This study investigated whether
misoprostol, prostaglandin E1 analogue, and OP-41483, prostaglandin I2
analogue, which have fewer adverse effects with a longer half-life, attenuate
ischemic liver damage. STUDY DESIGN: Thirty beagle dogs underwent 2 hours
of hepatic vascular exclusion using venovenous bypass. Misoprostol was
administered intravenously for 30 minutes before ischemia and for 3 hours
after reperfusion. OP-41483 was administered intraportally for 30 minutes
before ischemia (2 microg/kg/min) and for 3 hours after reperfusion (0.5
microg/kg/min). Animals were divided into five groups: untreated control group
(n=10); high-dose misoprostol (total 100 microg/kg) group (MP-H, n=5);
middle-dose misoprostol (50 microg/kg) group (MP-M, n=5); low-dose
misoprostol (25 microg/kg) group (MP-L, n=5); and OP-41483 group (OP, n=5).
Animal survival, hepatic tissue blood flow (HTBF), liver function, and histology
were analyzed. RESULTS: Two-week animal survival rates were 30% in control,
60% in MP-H, 100% in MP-M, 80% in MP-L, and 100% in OP. The treatments
with prostaglandin analogues improved HTBF, and attenuated liver enzyme
release, adenine nucleotrides degradation, and histologic abnormalities. In
contrast to the MP-H animals that exhibited unstable cardiovascular systems,
the MP-M, MP-L, and OP animals experienced only transient hypotension.
CONCLUSIONS: These results indicate that misoprostol and OP-41483
prevent ischemic liver damage, although careful dose adjustment of misoprostol
is required to obtain the best protection with minimal side effects.

Related Osteosarcoma Sites and Research Abstracts on Osteosarcoma and Radiation

http://www.msu.edu/~silvar/osteosarcoma.htmOSA
may have a heterogeneous appearance histologically and have been
classified as poorly differentiated, fibroblastic, osteoblastic,
telangectatic, giant cell, or chondroblastic based upon the
character of the neoplastic cell population and the type(s)
of matrix produced.12 OSA also may have a combined or mixed
appearance (e.g., a mixture of chondroid and osteoid matrix),
but newer classification schems place these neoplasms within
the osteoblastic subtype......Poorly differentiated and fibroblastic OSAs
have a pleomorphic to fusiform cell population with minimal
deposition of osteoid or production of bony spicules. Poorly
differentiated OSA is a highly aggressive neoplasm. Fibroblastic
OSA begins as a lytic tumor. Approximately 50% of these neoplasms
transition onto a combined type as the neoplastic spindle
cells begin to form matrix material. The fibroblastic type
of OSA has the most favorable prognosis.

Osteosarcoma" It
is known to metastasize soon after it is spawned in the marrow cavity and the most common site for
metastasis is the lung. Only about 10% of dogs are discovered to have obvious metastasis at the time of
initial diagnosis. However, regardless of how soon amputation is performed, the mortality rate is 90% in the
first year for animals receiving amputation alone. Apparently, factors associated with the primary tumor
prevent the micrometastases from growing. Knowledge of this behavior has resulted in the strategy of
instituting chemotherapy soon after removal of the primary tumor. This strategy has resulted in the
improved survival of nearly 50% of dogs for the first year and 20% for the second year following treatment.
The metastatic rate in cats is much lower. "

The role of angiostatin in the spontaneous bone and prostate cancers of pet
dogs.Angiostatin is a potent inhibitor of angiogenesis generated in cancer-bearing hosts by tumor-derived
proteases. Because the naturally occurring bone and prostate cancers of pet dogs provide unique
model systems to study factors that regulate cancer progression and tumor dormancy, we
investigated the capacity of these tumors to generate angiostatin. We determined that angiostatin
fragments are present in urine of dogs with bone cancer. The identity of these fragments was
confirmed by comparison of the experimentally determined protein sequence to that of a clone of
canine angiostatin. Importantly, these fragments were absent in urine collected from the same dogs
after complete surgical removal of the primary tumor. We also demonstrate that canine prostate
cancer cells are capable of processing plasminogen to angiostatin in vitro. These findings provide
rationale for using spontaneous canine tumor models to isolate endogenous angiogenesis inhibitors
and to investigate their therapeutic use against cancer.

Radiation therapy to a primary tumor accelerates metastatic growth in
mice. Radiation therapy to a primary tumor accelerates metastatic growth in
mice.
Camphausen K, Moses MA, Beecken WD, Khan MK, Folkman J, O'Reilly MS.
Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115, USA.
The surgical removal of a primary tumor can result in the rapid growth of metastases. The
production of angiogenesis inhibitors by the primary tumor is one mechanism for the inhibition of
metastatic tumor growth. The effect of curative radiotherapy to a primary tumor known to make an
inhibitor of angiogenesis and the effects on distant metastases has not been studied. We here show
that the eradication of a primary Lewis lung carcinoma (LLC-LM), which is known to generate
angiostatin, is followed by the rapid growth of metastases that kill the animal within 18 days after
the completion of radiation therapy. The right thighs of C57BL/6 mice (n = 25) were injected s.c.
with 1 x 10(6) LLC-LM cells. Animals were randomized to one of five groups: no irradiation, 40 Gy
in one fraction, 30 Gy in one fraction, 40 Gy in two 20 Gy fractions, or 50 Gy in five 10 Gy
fractions. Tumors were clinically eradicated in each treatment group. All of the surviving animals
became dyspneic and were killed within 14-18 days after the completion of radiation therapy.
Examination of their lungs revealed >46 (range, 46-62) surface metastases in the treated animals
compared with 5 (range, 2-8) in the untreated animals. The lung weights had increased from 0.2 g
(range, 0.19-0.22 g) in the controls to 0.58 g (range 0.44-0.84) in the experimental animals. The
most effective dose regimen was 10 Gy per fraction for five fractions, and serial experiments were
conducted with this fractionation scheme. Complete response of the primary tumor was seen in 25
of 35 (71%) mice. The average weight of the lungs in the nonirradiated animals was 0.22 g (range,
0.19-0.24 g) and in the irradiated animals was 0.66 g (range, 0.61-0.70 g). The average number of
surface metastases increased from five per lung (range, 2-13) in the control animals to 53 per lung
(range, 46-62) in the irradiated animals. Both differences were statistically significant with P <
0.001. If the nontumor-bearing leg was irradiated or the animals were sham-irradiated, no
difference in the number of surface metastases or lung weights was observed between the control
group and the treated group. Urinary levels of matrix metalloproteinase 2, the enzyme responsible
for angiostatin processing in this tumor model, were measured and correlated with the viability and
size of the primary tumor. Administration of recombinant angiostatin prevented the growth of the
metastases after the treatment of the primary tumor. In this model, the use of radiation to eradicate
a primary LLC-LM tumor results in the growth of previously dormant lung metastases and suggests
that combining angiogenesis inhibitors with radiation therapy may control distant metastases.Int J Oncol 2003 Jan;22(1):107-13
:
In vitro inhibition of growth and induction of apoptosis in cancer
cell lines by thymoquinone.
Shoieb AM, Elgayyar M, Dudrick PS, Bell JL, Tithof PK.
Department of Pathology, College of Veterinary Medicine, The University of
Tennessee, Knoxville, TN 37996-4543, USA.Thymoquinone (TQ) is likely responsible for the chemotherapeutic effects of N.
sativa extract; however, the cellular mechanisms remain ill-defined. TQ-induced
cytotoxicity was investigated using canine osteosarcoma (COS31), its
cisplatin-resistant variant (COS31/rCDDP), human breast adenocarcinoma (MCF7),
human ovarian adenocarcinoma (BG-1) and Madin-Darby canine (MDCK) cell lines.
TQ-induced cytotoxicity was determined using a proliferation assay (MTT assay)
and apoptosis assays. Effects of TQ on the cell cycle were determined using flow
cytometry. COS31/rCDDP resistant cells were the most sensitive cell line to TQ and
MDCK cells were the least sensitive. TQ (25 micro M) induced apoptosis of COS31
cells 6 h after treatment and decreased the number of COS31 cells in S-phase and
increased cells in G1-phase, indicating cell cycle arrest at G1. These results suggest
that TQ kills cancer cells by a process that involves apoptosis and cell cycle arrest.
Non-cancerous cells are relatively resistant to TQ.

A little on CACHEXIA-wasting

THERAPEUTIC DIET FOR DOGS WITH
LYMPHOMA
Inventor: OGILVIE, G K.; 2000
Brickwood Drive; Ft. Collins, CO
80525;
US; DAVENPORT, D
J.;1633 318 E. Road; Lecompton, KS
66050; US; GROSS, K L.; 3627 N.W.
94th Street;
Topeka, KS 66618; US; HAND, M S.;
Route 1, Box 430; Maple Hill, KS
66507; US;
Applicant:Colgate-Palmolive Company; 300 Park Avenue; New York, N.Y.
10022; US; ; Ogilvie,
Gregory K.; 2000 Brickwood Drive; Ft. Collins, CO 80525; US;
Appl. date 04 Oct 1996 publ. date 19 Dec 2001
The severity of metabolic disturbance in animals with cancer is
mitigated by feeding the animal a
nutritionally balanced food composition having a fat content of about
27 to 35 %, on a dry matter basis,
a carbohydrate content of about 15 to about 27 % on a dry matter basis
in which is present a mixture
of arginine, omega-3 polyunsaturated fatty acids and omega-6
polyunsaturated fatty acids, the weight
ratio of omega-3, omega-6 fatty acid being in the range of 0.3:1 to
3.5:1. Am J Surg 2002 Apr;183(4):471-9
:
Reversal of cancer-related wasting using oral supplementation
with a combination of beta-hydroxy-beta-methylbutyrate,
arginine, and glutamine.
May PE, Barber A, D'Olimpio JT, Hourihane A, Abumrad NN.
Department of Surgery/112, Veterans Affair Medical Center, 1000 Locust St.,
Reno, NV 85920, USA. peubanks@med.unr.eduBACKGROUND: Cancer-related cachexia is caused by a diverse combination of
accelerated protein breakdown and slowed protein synthesis. The hypothesis
proposed in this study is that supplementation of specific nutrients known to
positively support protein synthesis and reduce protein breakdown will reverse
the cachexia process in advanced cancer patients. METHODS: Patients with
solid tumors who had demonstrated a weight loss of at least 5% were considered
for the study. Patients were randomly assigned in a double-blind fashion to
either an isonitrogenous control mixture of nonessential amino acids or an
experimental treatment containing beta-hydroxy-beta-methylbutyrate (3 g/d),
L-arginine (14 g/d), and L-glutamine (14 g/d [HMB/Arg/Gln]). The primary
outcomes measured were the change in body mass and fat-free mass (FFM),
which were assessed at 0, 4, 8, 12, 16, 20, and 24 weeks. RESULTS: Thirty-two
patients (14 control, 18 HMB/Arg/Gln) were evaluated at the 4-week visit. The
patients supplemented with HMB/Arg/Gln gained 0.95 +/- 0.66 kg of body
mass in 4 weeks, whereas control subjects lost 0.26 +/- 0.78 kg during the same
time period. This gain was the result of a significant increase in FFM in the
HMB/Arg/Gln-supplemented group (1.12 +/- 0.68 kg), whereas the subjects
supplemented with the control lost 1.34 +/- 0.78 kg of FFM (P = 0.02). The
response to 24-weeks of supplementation was evaluated by an intent-to-treat
statistical analysis. The effect of HMB/Arg/Gln on FFM increase was
maintained over the 24 weeks (1.60 +/- 0.98 kg; quadratic contrast over time, P
<0.05). There was no negative effect of treatment on the incidence of adverse
effects or quality of life measures. CONCLUSIONS: The mixture of
HMB/Arg/Gln was effective in increasing FFM of advanced (stage IV) cancer.
The exact reasons for this improvement will require further investigation, but
could be attributed to the observed effects of HMB on slowing rates of protein
breakdown, with improvements in protein synthesis observed with arginine and
glutamine.Br J Nutr 2002 Dec;88(6):689-95
:
Evidence that glutamine modulates respiratory burst in stressed
rat polymorphonuclear cells through its metabolism into arginine.
Moinard C, Caldefie-Chezet F, Walrand S, Vasson MP, Cynober L.
Laboratoire de Biochimie, Biologie Moleculaire et Nutrition EA 2416 and
Centre de Recherche en Nutrition Humaine, Faculte de Pharmacie,
Clermont-Ferrand, France.Glutamine (GLN) and arginine (ARG) are recognized for their ability to
modulate immune cell function. However, the metabolic pathways involved in
their action remain unclear. It was recently shown that GLN- or ARG-enriched
diets increased radical oxygen species (ROS) production by neutrophils from
stressed rats. Since these two amino acids have a tied metabolism, we
hypothesized that conversion between GLN and ARG (and its active metabolites
NO* and polyamines) might be involved. To test this hypothesis male
Sprague-Dawley rats (n 117) were randomized into thirteen groups: rats in
eleven groups were rendered catabolic by dexamethasone injection (1.5 mg/kg
per d for 5 d) and 6.8 mmol either GLN, ARG or non-essential amino acids
(NEAA; glycine, alanine and histidine)/kg per d were given by the enteral
route; one group was pair-fed to the treated groups. The regimens of all the
groups were rendered isonitrogenous by the addition of NEAA. The last group
was not treated and was fed ad libitum. For each supplementation three
subgroups were formed, each of which received a specific inhibitor: methionine
sulfoximine (inhibitor of GLN synthase; 100 mg/kg per d), S-methylthiourea
(inhibitor of inducible NO* synthase (iNOS); 50 mg/kg per d) and
difluoromethylornithine (inhibitor of ornithine decarboxylase (ODC); 50 mg/kg
per d). Oxidative metabolism, intracellular H2O2, and extracellular O2*-
production were measured in unstimulated and phorbol myristate
acetate-stimulated polymorphonuclear neutrophils. GLN- and ARG-enriched
diets increased respiratory burst by neutrophils (oxidative metabolism of 152
(sem 24) and 138 (sem 45) v. 57 (sem 18) mV for GLN-, ARG- and
NEAA-enriched diets respectively, P<0.05). In vivo inhibition of iNOS or ODC
decreased ROS production induced by GLN and ARG. In vivo inhibition of GLN
synthase did not modify the effect of ARG on ROS production. In conclusion,
GLN and ARG modulate ROS production in neutrophils from stressed rats by
the same pathway involving polyamine and NO* synthesis.Crit Care Med 2002 Sep;30(9):2022-9
:
Comment in:
Crit Care Med. 2002 Sep;30(9):2152-3.
Glutamine supplementation in serious illness: a systematic review
of the evidence.
Novak F, Heyland DK, Avenell A, Drover JW, Su X.
Department of Medicine, Queens University, Kingston General Hospital,
Ontario, Canada.OBJECTIVE: To examine the relationship between glutamine supplementation
and hospital length of stay, complication rates, and mortality in patients
undergoing surgery and experiencing critical illness. DATA SOURCES:
Computerized search of electronic databases and search of personal files,
abstract proceedings, relevant journals, and review of reference lists. STUDY
SELECTION: We reviewed 550 titles, abstracts, and articles. Primary studies
were included if they were randomized trials of critically ill or surgical
patients that evaluated the effect of glutamine vs. standard care on clinical
outcomes.DATA EXTRACTION We abstracted relevant data on the
methodology and outcomes of primary studies in duplicate, independently.DATA
SYNTHESIS There were 14 randomized trials comparing the use of glutamine
supplementation in surgical and critically ill patients. When the results of these
trials were aggregated, with respect to mortality, glutamine supplementation
was associated with a risk ratio (RR) of 0.78 (95% confidence interval [CI],
0.58-1.04). Glutamine supplementation was also associated with a lower rate of
infectious complications (RR, 0.81; 95% CI, 0.64-1.00) and a shorter hospital
stay (-2.6 days; 95% CI, -4.5 to -0.7). We examined several -specified
subgroups. Although there were no statistically significant subgroup
differences detected, there were some important trends. With respect to
mortality, the treatment benefit was observed in studies of parenteral
glutamine (RR, 0.71; 95% CI, 0.51-0.99) and high-dose glutamine (RR, 0.73;
95% CI, 0.53-1.00) compared with studies of enteral glutamine (RR, 1.08; 95%
CI, 0.57-2.01) and low-dose glutamine (RR, 1.02; 95% CI, 0.52-2.00). With
respect to hospital length of stay, all of the treatment benefit was observed in
surgical patients (-3.5 days; 95% CI, -5.3 to -1.7) compared with critically ill
patients (0.9 days; 95% CI, -4.9 to 6.8). CONCLUSION: In surgical patients,
glutamine supplementation may be associated with a reduction in infectious
complication rates and shorter hospital stay without any adverse effect on
mortality. In critically ill patients, glutamine supplementation may be
associated with a reduction in complication and mortality rates. The greatest
benefit was observed in patients receiving high-dose, parenteral glutamine.
Cancer 2003 Apr 1;97(7):1732-6 :
Risk of lung carcinoma among users of nonsteroidal antiinflammatory drugs.
Muscat JE, Chen SQ, Richie JP Jr, Altorki NK, Citron M, Olson S, Neugut AI, Stellman SD.
American Health Foundation, Valhalla, New York 10595, USA. jmuscat@ahf.org
BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit
the development of lung tumors in experimental animals. To the authors' knowledge
there are little data regarding whether regular use of NSAIDs reduces the
risk of developing lung carcinoma in humans. METHODS: The association between
lung carcinoma risk and regular use of NSAIDs, including aspirin, was evaluated
in a hospital-based case-control study of 1038 patients and 1002 controls.
RESULTS: The relative risk estimate of lung carcinoma associated with using
NSAIDs 3 times a week or more for 1 or more years demonstrated an odds ratio
(OR) of 0.68 (95% confidence interval [95% CI], 0.53-0.89). Results were
similar when separated by lung histologic type. The association varied by
smoking status. The OR was 1.28 (95% CI, 0.73-2.25) in never-smokers and
0.60 (95% CI 0.45-0.80) in ever-smokers. The smoking-specific risk estimates
for aspirin were similar to those for all NSAIDs. CONCLUSIONS: The results
of the current study suggest a possible chemoprotective benefit with the
use of NSAIDs among individuals who are former or current smokers. Copyright
2003 American Cancer Society.DOI 10.1002/cncr.11242 J Nutr 2002 Dec;132(12):3804S-3808S :
Short chain fatty acids and colon cancer.
Augenlicht LH, Mariadason JM, Wilson A, Arango D, Yang W, Heerdt BG, Velcich A.
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY 10467, USA. augen@aecom.yu.edu
The development of intestinal cancer involves complex genetic and
epigenetic alterations in the intestinal mucosa. The principal signaling
pathway responsible for the initiation of tumor formation, the APC-beta-catenin-TCF4
pathway, regulates both cell proliferation and colonic cell differentiation,
but many other intrinsic and extrinsic signals also modulate these cell maturation
pathways. The challenge is to understand how signaling and cell maturation
are also modulated by nutritional agents. Through gene expression profiling,
we have gained insight into the mechanisms by which short chain fatty acids
regulate these pathways and the differences in response of gene programs,
and of the specific regulation of the c-myc gene, to physiological regulators
of intestinal cell maturation, such as butyrate, compared with pharmacological
regulators such as the nonsteroidal antiinflammatory drug sulindac. Moreover,
we used a combination of gene expression profiling of the response of cells
in culture to sulindac and the response of the human mucosa in subjects treated
with sulindac for 1 month, coupled with a mouse genetic model approach, to
identify the cyclin dependent kinase inhibitor p21(WAF1/Cip1) as an important
suppressor of Apc-initiated intestinal tumor formation and a necessary component
for tumor inhibition by sulindac. Finally, the mucous barrier, secreted by
intestinal goblet cells, is the interface between the luminal contents and
the intestinal mucosa. We generated a mouse genetic model with a targeted
inactivation of the Muc2 gene that encodes the major intestinal mucin. These
mice have no recognizable goblet cells due to the failure of cells to synthesize
and store mucin. This leads to perturbations in intestinal crypt architecture,
increased cellular proliferation and rates of cell migration, decreased apoptosis
and development of adenomas and adenocarcinomas in the small and large intestine
and the rectum. JPEN J Parenter Enteral Nutr 2002 Sep-Oct;26(5):285-9 :
Comment in:
JPEN J Parenter Enteral Nutr. 2002 Sep-Oct;26(5):290.
Omega-3 fatty acid supplementation reduces tumor growth and vascular endothelial
growth factor expression in a model of progressive non-metastasizing malignancy.
Tevar R, Jho DH, Babcock T, Helton WS, Espat NJ.
Department of Surgery, University of Illinois at Chicago, 60612, USA.
BACKGROUND: Omega-3 fatty acids, the principal component of fish
oil, have been demonstrated to have antiinflammatory properties. The role
of eicosapentaenoic acid (EPA) supplementation for cancer patients is currently
under investigation; however, the mechanisms of EPA activity have not been
defined. The purpose of this study was to characterize tumor-specific and
treatment-specific effects of supplemental dietary EPA in an animal model
of progressive malignancy. METHODS: Fischer 344 rats (200-250 g) underwent
flank implantation of the methycholanthrene (MCA)-induced fibrosarcoma on
day 0. Rats were randomly divided into 3 treatment groups on day 13: EPA
(1 mL, 5.0 g/kg per day) + 10 IU vitamin E; corn oil (1 mL) + 10 IU vitamin
E, and saline (1 mL) + 10 IU vitamin E (vitamin E was used to prevent fatty
acid oxidation). On day 14, gavage feeding was started and was continued
through day 28. The animals were killed on day 29, and the tumors were removed.
The tumors were weighed and divided by the tumor-free carcass weight to obtain
percentage of tumor volume, and the livers were flash frozen. Vascular endothelial
growth factor-alpha (VEGF-alpha) and cyclo-oxygenase 2 (COX-2) mRNA were
measured by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS:
EPA rats had significant reductions in tumor volume compared with isocaloric
corn oil and control saline animals (25%, p < .01 and 33%, p < .01,
respectively). Rats receiving EPA demonstrated decreased VEGF-alpha mRNA
levels (0.023 +/- 0 0.001) compared with those receiving corn oil (0.129
+/- 0.047) or saline (0.150 +/- 0.026; p < .05). CONCLUSIONS: These data
demonstrate that EPA supplementation inhibits tumor growth, potentially through
alterations in the expression of the pro-angiogenic VEGF-alpha. The mechanism(s)
of EPA as an inhibitor of tumor-related angiogenic growth factors may be
associated with COX-2 enzyme fatty acid metabolism and merits further study.